title: Functional and molecular genetic analyses of nine newly identified XPD-deficient patients reveal a novel mutation resulting in TTD as well as in XP/CS complex phenotypes.
abstract: The xeroderma pigmentosum (XP) group D protein is involved in nucleotide excision repair (NER) as well as in basal transcription. Determined by the type of XPD mutation, six different clinical entities have been distinguished: XP, XP with neurological symptoms, trichothiodystrophy (TTD), XP⁄TTD complex, XP⁄Cockayne syndrome (CS) complex or the cerebro-oculo-facio-skeletal syndrome (COFS). We identified nine new XPD-deficient patients. Their fibroblasts showed reduced post-UV cell survival, reduced NER capacity, normal XPD mRNA expression and partly reduced XPD protein expression. Six patients exhibited a XP phenotype in accordance with established XP-causing mutations (c.2079G>A, p.R683Q; c.2078G>T, p.R683W; c.1833G>T, p.R601L; c.1878G>C, p.R616P; c.1878G>A, p.R616Q). One TTD patient was homozygous for the known TTD-causing mutation p.R722W (c.2195C>T). Two patients were compound heterozygous for a TTD-causing mutation (c.366G>A, p.R112H) and a novel p.D681H (c.2072G>C) amino acid exchange, but exhibited different TTD and XP/CS complex phenotypes, respectively. Interestingly, the XP/CS patient's cells exhibited a reduced but well detectable XPD protein expression compared with hardly detectable XPD expression of the TTD patient's cells. Same mutations with different clinical outcomes in NER-defective patients demonstrate the complexity of phenotype-genotype correlations, for example relating to additional genetic variations (parental consanguinity), different allelic expression due to SNPs or differences in the methylation status.
authors.forename: Annika
authors.initials: A
authors.lastname: Schäfer
authors.forename: Alexei
authors.initials: A
authors.lastname: Gratchev
authors.forename: Christina
authors.initials: C
authors.lastname: Seebode
authors.forename: Lars
authors.initials: L
authors.lastname: Hofmann
authors.forename: Steffen
authors.initials: S
authors.lastname: Schubert
authors.forename: Petra
authors.initials: P
authors.lastname: Laspe
authors.forename: Antje
authors.initials: A
authors.lastname: Apel
authors.forename: Andreas
authors.initials: A
authors.lastname: Ohlenbusch
authors.forename: Mladen
authors.initials: M
authors.lastname: Tzvetkov
authors.forename: Carsten
authors.initials: C
authors.lastname: Weishaupt
authors.forename: Vinzenz
authors.initials: V
authors.lastname: Oji
authors.forename: Michael P
authors.initials: MP
authors.lastname: Schön
authors.forename: Steffen
authors.initials: S
authors.lastname: Emmert
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003057:Cockayne Syndrome / Q000235:genetics*; D004260:DNA Repair; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D054463:Trichothiodystrophy Syndromes / Q000235:genetics*; D014983:Xeroderma Pigmentosum / Q000235:genetics*; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics*; D055815:Young Adult
chemical_list: D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human